Immunotherapy for advanced cervical cancer - PowerPoint Presentation

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Immunotherapy for advanced cervical cancer

Megan Swanson, MD MPH

Assistant Professor

Gynecologic Oncology

UCSF

Limited effective treatment options for advanced cervical cancer

Problem

: when cervical cancer is advanced and/or recurrent without curative surgical or radiation options, systemic therapy options are limited

Standard of Care

Chemotherapy + VEGF inhibitor: cisplatin/paclitaxel/bevacizumab

Response rate 48%Median overall survival (OS) 17 months

Cervical Cancer and HPV

Almost all cervical cancer related to HPV infection

High-risk HPV strains (16/18) are more likely to persist and integrate into host genome, leading to excess production oncoproteins E6/E7

Immunotherapy and cervical cancer

Immune therapy is a promising treatment for cervical cancer

Active vaccination may induce immune responseCheckpoint inhibitors are now approved in the treatment of recurrent cervical cancer and combination checkpoint inhibition have demonstrated responses that are better than current chemotherapy options. Tumor Infiltrating Lymphocytes – promising new cell transfer therapy

Active vaccines

Differ from prophylactic HPV vaccination, very effective in preventing cervical dysplasia and cancer

Investigations of novel therapeutic vaccines targeting both cervical dysplasia and cervical cancer are ongoing. A preclinical trial utilizing showed promising results in a mouse model and was associated with longer survival and greater production of HPV16 E7-specific CD8+ T cells

Pembrolizumab (Keytruda) – PD1 inhibitor

Expression of PD-L1 by tumors allows the tumor to escape cell destruction by CD8+ killer T cells.

Pembrolizumab binds to the PD-1 receptor, blocking the interaction of this receptor with the ligand (PDL1), unmasking the immune responseKEYNOTE 028: response rate 17%, OS 11 mo KEYNOTE 158: response rate 15% in PDL1+ tumors, OS 11mo, median duration of response was not reached Given KEYNOTE 158 results and high unmet need, FDA granted accelerated approval of pembrolizumab for patients with previously treated recurrent PDL1+ cervical cancer

Dual checkpoint inhibitors: PD1 inhibitors with CTLA4 inhibitors

CheckMate-358: nivolumab & ipilimumab - significant activity in treatment of metastatic cervical cancerResponse rates up to 46% (34% in those with previously-treated disease)OS 25mo for those with prior treatment, not reached for those without prior treatment (durable!)

(data not yet published, presented at ESMO 2019)

Is dual checkpoint inhibition better than single-agent PD1 inhibition?

We will find out! Open trial at UCSF (GOG 3028):

RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer

What about combining immunotherapy with standard-of-care chemotherapy + VEGF inhibitor (GOG 240 regimen)?

KEYNOTE 826

: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy Versus Chemotherapy Plus Placebo for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical CancerChemotherapy: paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg every 3 weeksContinue for up to 2 years or progression/toxicityBEATcc: A Randomized Phase III Trial of Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab Versus Platinum Chemotherapy Plus Paclitaxel and Bevacizumab in Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the CervixChemotherapy: Cisplatin 50mg/m2 or carboplatin AUC 5 + paclitaxel 175mg/m2+ bevacizumab 15 mg/kg every 3 weeksPatients who achieve a complete response after ≥6 treatment cycles may be allowed to continue only on biologics therapy, namely bevacizumab plus atezolizumab

Tumor Infiltrating Lymphocytes (TIL)

LN-145 (

lovance Biotherapeutics) is an adoptive cell transfer therapy that utilizes an autologous TIL manufacturing process (originally developed by the NCI) for the treatment of patients with advanced cervical cancer TILs are extracted (need large amount of tumor) and expanded in the laboratory. These TILs are then reinfused after marrow ablative chemotherapy. Complete and durable responses have been observed